Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits  Chen Yao, Roby Joehanes, Andrew D. Johnson, Tianxiao Huan, Chunyu Liu, Jane E. Freedman, Peter J. Munson, David E. Hill, Marc Vidal, Daniel Levy  The American Journal of Human Genetics  Volume 100, Issue 4, Pages 571-580 (April 2017) DOI: 10.1016/j.ajhg.2017.02.003 Copyright © 2017 Terms and Conditions

Figure 1 Work Flow and Results Summary 42,271 SNPs associated with 1,960 traits were obtained from GRASP (at p ≤ 5 × 10−8). Whole blood samples were collected from 5,257 FHS participants. Genome-wide genotyping and mRNA expression levels were assayed. We correlated 39,165 GWAS SNPs (after filtering) with expression levels of 17,873 genes to identify expression quantitative trait loci (eQTLs). For SNPs having both local (cis) and remote (trans) regulation effects, we then tested whether the effect of trans-eQTLs was mediated through cis-eGenes. Finally, integrating genotype, gene expression, and phenotype data, we conducted causal inference testing to identify causal variants for eight cardiometabolic traits (BMI, systolic and diastolic blood pressure, LDL cholesterol, HDL cholesterol, total cholesterol, triglycerides, fasting blood glucose). The American Journal of Human Genetics 2017 100, 571-580DOI: (10.1016/j.ajhg.2017.02.003) Copyright © 2017 Terms and Conditions

Figure 2 Mediation Mechanisms of eQTLs Genetic variants can affect traits through the following mechanisms: (1) missense SNP affects protein structure/function; (2) non-coding SNP affects gene expression (cis); (3) non-coding SNP affects remote (trans) gene expression directly or by (4) cis-eGene mediation of the trans-eQTL-trans-eGene association; or (5) reverse causality (trait has feedback effect on gene expression). The American Journal of Human Genetics 2017 100, 571-580DOI: (10.1016/j.ajhg.2017.02.003) Copyright © 2017 Terms and Conditions

Figure 3 trans-eQTL Hotspots x axis denotes the chromosomal location of SNPs. y axis denotes the number of trans-eGenes. The American Journal of Human Genetics 2017 100, 571-580DOI: (10.1016/j.ajhg.2017.02.003) Copyright © 2017 Terms and Conditions

Figure 4 cis- and trans-eQTLs in the ALDH2 Causal Module Gray boxes list traits associated with SNPs from GWASs, green boxes list SNPs, red box lists the cis-eGene, and blue boxes list trans-eGenes. Red edges represent cis-associations; green edges represent trans-associations. The American Journal of Human Genetics 2017 100, 571-580DOI: (10.1016/j.ajhg.2017.02.003) Copyright © 2017 Terms and Conditions